Fulminant hepatic failure (FHF), defined as severe hepatocellular dysfunction in which encephalopathy occurs within eight weeks of the onset of symptoms (Bernau, J. et al. Sem. Liv. Dis. 6:97-106 (1986); Yanda, R. J. West. J. Med. 149:586-591 (1988); Katelaris, P. H. et al. Med. Clinics N. Amer. 73:955-970 (1989)), is generally caused by viral hepatitis, drug reactions or poisoning. In the absence of liver transplantation, the survival rate is about 20% but varies dramatically (from 6 to 79%) depending on age of the patient and etiology of the disease (Bernau et al., supra; Yanda, supra; Katelaris et al., supra).
The clinical course of FHF is influenced by the onset of multi-organ failure and mortality increases with the onset of severe clotting abnormalities, renal failure, pulmonary edema or cardiovascular collapse (Bihari, D. J. et al. Sem. Liv. Dis. 6:119-128 (1986)). The development of multi-organ failure is the result of circulating toxins such as mercaptans, phenols, fatty acids, ammonia and molecules which increase vascular permeability (Bernau et al., supra; Yanda, supra; Katelaris et al., supra). The most severe consequence of this increased permeability is seen in the brain. Toxins cross the blood-brain barrier and produce effects like the inhibition of Na.sup.+ -K.sup.+ ATPase and a depression of the level of consciousness by occupation of the GABA-benzodiazepine receptor (Bassett, D. J. et al. Gastroenterology 93:1069-1077 (1987)). The final step in this progressive central nervous system disturbance is cerebral edema, the most common cause of death in FHF (Ede, R. J. et al. Sem. Liv. Dis. 6:107-118 (1986)).
Orthotopic liver transplantation is an effective treatment for a wide variety of conditions that destroy hepatic function ranging from genetic defects to tumors (Starzl, T. E. et al. N. Engl. J. Med. 321:1014-1022 (1989)). This is an increasingly popular treatment in the United States, with approximately 2000 transplants per year and an expected rise to 4000 per year within the next few years in the U.S. and a similar number in Europe. It has been estimated that, were the financial and medical resources available, the actual need could reach as high as 50,000 liver transplants per year in the U.S. alone.
One of the major problems with transplantation is the fairly fine distinction between a sufficient and insufficient amount of liver function. For example, a rat typically survives a 70% hepatectomy whereas removal of 80% of the liver is generally lethal. The consequence of this fact is that patients frequently enter into FHF precipitously. Since no satisfactory method for artificial liver support is currently available, therapeutic decisions are often made on the basis of locally available medical resources and without the ability to obtain consent of the patient.
The reversal of multi-organ failure by orthotopic liver transplantation has made it the standard of therapy against which other therapeutic modalities will have to be measured. Liver transplantation has been advocated in all patients who present in FHF based on the observation that, when transplantation was delayed until its need became obvious, 60% of patients died.
This possibly overzealous view ignores the fact that FHF is not uniformly fatal. Groups with a relatively good prognosis, such as acetaminophen poisoning patients, have been identified. Since recovery from FHF is usually associated with the return of normal liver function, and transplantation commits the patient to lifelong medical supervision and immunosuppression, early transplantation cannot be considered the best option unless a fatal outcome can be predicted early in the course of illness.
On the other hand, emergency transplantation is also unsatisfactory. Patients entering stage III coma are at an immediate increased risk of death, with their condition often deteriorating rapidly. This may necessitate transplanting a liver from an incompatible donor. Indeed, several deaths due to failed organ procurement have been reported (Vickers, C. et al. J. Hepatol. 7:143-150 (1988); Esmond, J. C. et al. Gastroenterology 96:1583-1588 (1989)).
Emergency orthotopic liver transplantation is currently the only method of acute liver support known in the art. It has a high mortality rate, a prohibitive cost, and a significant negative impact on the patient's quality of life. An alternative method of supporting liver function would be highly desirable in that it could provide sufficient time for liver regeneration to occur. The benefit to the individual is beyond any reasonable calculation, but the financial savings amount to hundreds of thousands of dollars; the actual cost of the transplant alone is between $70,000 and $240,000 depending on the condition of the patient (Dindzans, V. J. et al. Dig. Dis. and Sci. 34:161-166 (1989)).
Since secondary liver damage may be caused by circulating toxins, early hepatic support may also improve the internal milieu thereby promoting liver regeneration. In cases where regeneration does not occur, liver support will forestall or prevent multi-organ failure. Thus, the fear of "watching" the patient too long and the death of patients awaiting a donor would be minimized by the availability of a liver assist device. Furthermore, only patients whose livers fail to regenerate will be transplanted, and improvement of general health prior to liver transplantation surgery is correlated with improved survival.
In 10 to 20% of liver transplants, the transplanted liver fails on reperfusion. These patients then require emergency second transplants. The availability of an extracorporeal liver assist device would allow them to recover before undergoing a second round of major surgery. A means of supporting liver function is therefore urgently required.
The use of artificial support devices has had dramatic effect on kidney, heart and lung transplantation, but no such device is available for liver support. There remains, therefore, the need for a supportive system for long-term preservation of liver functions. Such a liver assist device would have application in a number of transplant situations. First, it would allow patients in fulminant hepatic failure to be stabilized and calmly evaluated before operating. Second, it finds use in stabilizing and assisting patients after transplant, particularly in situations in which the graph fails to respond on reperfusion. Third, in some instances it may serve as a substitute for transplant. The device would allow time for the patient's natural liver to regenerate, sparing the expense of operation, the life long dependence on immunosuppression and the likelihood of premature mortality.